Genetic and cytological characterization of the recombination protein RAD-51 in Caenorhabditis elegans

Alpi, Arno F.; Pasierbek, Paweł; Gartner, Anton; Loidl, Josef

doi:10.1007/s00412-003-0237-5

Cited by 230 publications

(267 citation statements)

References 62 publications

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“…As a consequence, oocytes that are not eliminated by apoptosis in rad-51 mutants display chromatin diffusion and fragmented DNA in diakinesis. 3,30 Surprisingly, rad-51;msh-4 double mutants maintain the same high level of germ-nuclei apoptosis seen in the rad-51 single mutant (Figure 7b), suggesting that the MSH-4/5 dependency of the apoptotic response requires the presence of RAD-51-dependent recombination intermediates.…”

Section: Resultsmentioning

confidence: 83%

Pro-crossover factors regulate damage-dependent apoptosis in the Caenorhabditis elegans germ line

et al. 2013

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During meiosis, DNA double-strand breaks (DSBs) are physiologically induced to start the recombination process and promote the formation of interhomologue crossovers (COs), which are required to ensure faithful chromosome segregation into the gametes. The timely repair of DSBs is an essential part of the meiotic programme, as accumulation of unprocessed DSBs during the pachytene stage of meiotic prophase triggers a DNA damage checkpoint response that induces apoptosis of damaged cells. We show that CO-promoting factors MSH-4, MSH-5, and ZHP-3, but not COSA-1, are required for the apoptotic response of the meiotic DNA damage checkpoint. Lack of MSH-4 or MSH-5 suppresses the apoptotic response observed in some DNA repairdefective mutants such as fcd-2 and brc-1 (orthologues of FANCD2 and BRCA1), irrespectively of the amount of DSBs present in pachytene nuclei. Although ionizing radiation fails to induce apoptosis in msh-4/5-mutant backgrounds, it induces transcriptional activation of the apoptosis-activator egl-1, which is controlled by the Caenorhabditis elegans p53 orthologue CEP-1. This finding suggests that MSH-4/5 involvement in the apoptotic response occurs downstream or independently of damage sensing and checkpoint activation. This study establishes a role for pro-CO factors MSH-4/5 and ZHP-3 in the execution of apoptosis at late meiotic prophase following the accumulation of exogenous or endogenous DNA damage. Cell Death and Differentiation (2013) 20, 1209-1218; doi:10.1038/cdd.2013.68; published online 5 July 2013Eukaryotes execute meiosis to ensure the proper partition of chromosomes into the gametes. Crossing-overs (COs) between homologous chromosomes are essential, along with sister chromatid cohesion, to ensure proper chromosome segregation at meiosis I. All studied organisms exhibit an excess of double-strand breaks (DSBs), generated by type II topoisomerase-like SPO-11, with just a few being ultimately repaired as interhomologue COs. Once DSBs arise, they undergo resection to produce single-stranded DNA, a substrate for the loading of the recombinase RAD-51. This protein, homologous to the Escherichia coli recombinase RecA, promotes strand exchange and invasion of the homologous DNA template, allowing homologous DNA repair to take place. 1 Faithful repair of DSBs during meiosis is crucial to maintain genomic integrity and to allow formation of functional gametes, as unrepaired DSBs trigger activation of the DNA damage checkpoint, which results in a block to cell cycle progression or removal of damaged cells by apoptosis. 2 The Caenorhabditis elegans germ line exhibits a complete time course of meiotic prophase in which nuclei at the different stages of oogenesis can be easily identified based on their position and appearance, and it has been shown that DSB repair is differently modulated along the germ line. For example, loading of RAD-51, the only RecA-like protein responsible for the strand exchange step in C. elegans meiosis, 3,4 is RAD-50 independent in the premeiotic region of the germ line an...

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Section: Resultsmentioning

confidence: 83%

Pro-crossover factors regulate damage-dependent apoptosis in the Caenorhabditis elegans germ line

et al. 2013

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“…This phenotype is reminiscent to that of msh-5 mutants. Genetic and cytological evidence indicated that MSH-5 acts after the initiation of recombination (4,28,44). Like MSH-5, HIM-6 could act after the initiation of recombination and might be necessary for a late step of recombination (Fig.…”

Section: Discussionmentioning

confidence: 99%

Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line

Wicky

Alpi

Passannante

et al. 2004

Molecular and Cellular Biology

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Bloom's syndrome (BS) is an autosomal-recessive human disorder caused by mutations in the BS RecQ helicase and is associated with loss of genomic integrity and an increased incidence of cancer. We analyzed the mitotic and the meiotic roles of Caenorhabditis elegans him-6, which we show to encode the ortholog of the human BS gene. Mutations in him-6 result in an enhanced irradiation sensitivity, a partially defective S-phase checkpoint, and in reduced levels of DNA-damage induced apoptosis. Furthermore, him-6 mutants exhibit a decreased frequency of meiotic recombination that is probably due to a defect in the progression of crossover recombination. In mitotically proliferating germ cells, our genetic interaction studies, as well as the assessment of the number of double-strand breaks via RAD-51 foci, reveal a complex regulatory network that is different from the situation in yeast. Although the number of double-strand breaks in him-6 and top-3 single mutants is elevated, the combined depletion of him-6 and top-3 leads to mitotic catastrophe concomitant with a massive increase in the level of double-strand breaks, a phenotype that is completely suppressed by rad-51. him-6 and top-3 are thus needed to maintain low levels of double-strand breaks in normally proliferating germ cells, and both act in partial redundant pathways downstream of rad-51 to prevent mitotic catastrophy. Finally, we show that topoisomerase III␣ acts independently during a late stage of meiotic recombination.

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“…9.4 , lowest panels). The recombination checkpoint can be triggered, even when only a single meiotic chromosome fails to pair (Colaiacovo et al 2003 ;Alpi et al 2003 ;Mets and Meyer 2009 ) . In those pairing defective mutants apoptosis is thought to be triggered by the excessive SPO-11-generated double-strand breaks, which in the absence of a homologous chromosome fail to be repaired (Fig.…”

Section: Meiotic Recombination Checkpoint and Template Preferencementioning

confidence: 99%

“…In wildtype spo-11 -dependent RAD-51 foci are generated in the transition zone and are generally repaired in the early and mid-pachytene stages. In pairing defective mutants, foci stay, but appear to be repaired in the very late pachytene stage (independent of non-homologous end-joining), likely by sister chromatid templated repair (Adamo et al 2008 ;Colaiacovo et al 2003 ;Alpi et al 2003 ) . It is intriguing that germ cell apoptosis induction also affects these very late-stage pachytene cells.…”

Section: Meiotic Recombination Checkpoint and Template Preferencementioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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Genetic and cytological characterization of the recombination protein RAD-51 in Caenorhabditis elegans

Cited by 230 publications

References 62 publications

Pro-crossover factors regulate damage-dependent apoptosis in the Caenorhabditis elegans germ line

Pro-crossover factors regulate damage-dependent apoptosis in the Caenorhabditis elegans germ line

Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line

Germ Cell Apoptosis and DNA Damage Responses

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